Carbonylbisphosphonic acid

The esters also react readily with aryl hydrazines to give aryl hydrazone derivatives. Examples of the latter were first synthesized (prior to the availability of tetraalkyl carbonylphosphonates) from tetraalkyl methylenebisphosphonates and aryl diazonium salts, analogously to the phosphonoglyoxylate hydrazone synthesis described in a previous section. First made as possible precursors in a ketone synthesis, several of these compounds, converted to free acid salts by treatment with BTMS followed by dicyclohexylamine in methanol, proved to have unexpected inhibitory activity vs the pyrophosphate-dependent phospho-fructokinase of the parasite T. gondii, which causes a potentially lethal opportunistic infection in immunocompromised persons such as AIDS patients [94]. In fact, the 2,4-dinitrophenylhydrazone of carbonylbisphosphonic acid (as the tetrasodium salt) dramatically abated toxoplasmosis lesions in infected human foreskin fibroblasts [94]. Animal toxicity in this compound, probably arising from in vivo hydrolysis to the highly toxic hydrazine, precluded its future development, but the result remains an interesting lead. 

The tetrasodium salt of carbonylbisphosphonate was originally synthesized by Quimby et al. [76], using hydrolysis of a tetraalkyl dichloromethylenebisphos-phonate in aqueous NaOH. In aqueous solution, the yellow ketone form reversibly converts to its colorless hydrate at acidic pH [76], a process which can be assessed by a combination of 31P-NMR and uv-visible spectroscopy at pH 7, the ketone predominates [93]. The salt moderately inhibits HIV reverse transcriptase in a p24 assay, whereas the parent methylene compound is inactive [64], displays some activity vs the pyrophosphate-dependent phosphofructose kinase of the parasite T. gondii [94] and has found use as a selective inhibitor of PCNA-independent DNA polymerase 6, allowing its enzyme activity to be distinguished from that of DNA polymerase a [95]. 

Carbonylbisphosphonate esters react smoothly with NH2OCH3. For example, reaction of the isopropyl ester gave the corresponding stable O-methyl oxime in 60% yield. The free oximes, and the corresponding oxime derivatives of acid bis-phosphonates, have not yet been subjected to systematic study. However, very preliminary work indicates that the free oxime of the parent acid in aqueous solution is unstable to fragmentation with C-P bond cleavage, similar to that encountered with the troika acids. 

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